An integrated genomic and transcriptomic survey of mucormycosis-causing fungi.

Chibucos MC1,2, Soliman S3, Gebremariam T3, Lee H3, Daugherty S2, Orvis J2, Shetty AC2, Crabtree J2, Hazen TH1,2, Etienne KA4, Kumari P2, O'Connor TD2,5, Rasko DA1,2, Filler SG3,6, Fraser CM2, Lockhart SR4, Skory CD7, Ibrahim AS3,6, Bruno VM1,2.

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Abstract

Mucormycosis is a life-threatening infection caused by Mucorales fungi. Here we sequence 30 fungal genomes, and perform transcriptomics with three representative Rhizopus and Mucor strains and with human airway epithelial cells during fungal invasion, to reveal key host and fungal determinants contributing to pathogenesis. Analysis of the host transcriptional response to Mucorales reveals platelet-derived growth factor receptor B (PDGFRB) signaling as part of a core response to divergent pathogenic fungi; inhibition of PDGFRB reduces Mucorales-induced damage to host cells. The unique presence of CotH invasins in all invasive Mucorales, and the correlation between CotH gene copy number and clinical prevalence, are consistent with an important role for these proteins in mucormycosis pathogenesis. Our work provides insight into the evolution of this medically and economically important group of fungi, and identifies several molecular pathways that might be exploited as potential therapeutic targets.